Here are some preferences that you may wish to set initially. The full list and explanation of the Preferences are documented in the section Preferences.
Enable, and choose the Language and what to translate from Interface, Tooltips and New Data.
See Translation for details.
If you have a compact keyboard without a separate number pad, enable.
If you do not have a middle mouse button, you can enable.
See Input Preferences for details.
File and Paths
Atyou can set options such as what external Image Editor to use, such as GIMP or Krita, and the Animation Player.
The Temporary Directory sets where to store files such as temporary renders and auto-saves.
// at the start of each path in Blender means the directory of the currently opened blend-file,
used to reference relative paths.
See File Preferences for details.
Save & Load
If you trust the source of your blend-files, you can enable Auto Run Python Scripts. This option is meant to protect you from malicious Python scripts that someone can include inside a blend-file. This would not happen by accident, many users leave this option on to automatically run scripts often used in advanced rigs (such as "Rigify" that controls the skeleton of a human rig).
See Save & Load Auto Run Python Scripts Preference.